TRAF3IP2-AS1 Gene

The TRAF3IP2-AS1 gene is a protein-coding gene located on chromosome 6q21. The TRAF3IP2 gene encodes Act1, an adaptor protein with ubiquitin ligase activity that links the IL-17 receptor to downstream signaling pathways.

The protein encoded by the TRAF3IP2 gene, Act1 is an important adaptor in the IL-17A signaling pathway. A long noncoding anti-sense RNA, TRAF3IP2-AS1, has been shown to regulate Act1 expression and IL-17A signaling by recruiting SRSF10, which in turn downregulates the expression of IRF1, a transcription factor of Act1 (He R et al. 2021). A variant of TRAF3IP2-AS1 A4165G (rs13210247) that is significant for psoriasis is a gain-of-function mutant.

Gene ontology analysis shows that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with genes of early differentiation (KRT1, KRT10, DSC1, DSG1) downregulated and genes of late differentiation (SPRR2, SPRR3, LCE3) upregulated. Many genes involved in host defense are induced by IL-17 in a TRAF3IP2-dependent manner. These results suggest that TRAF3IP2 alters both epidermal homeostasis and keratinocyte defense responses (Lambert S et al. 2017).

Polymorphisms in the TRAF3IP2 gene are associated with psoriatic arthritis and psoriasis.

An autosomal recessive ACT1 deficiency caused by heterozygous variants in the TRAF3IP2 gene (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) resulted in impaired NF-κB activation associated with the clinical picture of chronic mucocutaneous candidiasis (Blanco Lobo P et al. 2021).

Approximately half of the cases of familial CMC carry STAT1 gain-of-function (GOF) mutations. Few patients are known to have mutations of TRAF3IP2, a gene encoding the adaptor ACT1, which is important for IL-17 receptor (R) signaling (Blanco Lobo P et al. 2021)

Many results suggest that TRAF3IP2-AS1 and/or SRSF10 may represent attractive therapeutic targets for the treatment of IL-17-related autoimmune diseases such as psoriasis and multiple sclerosis (He R et al. 2021).

1. Blanco Lobo P et al (2021) Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant. Pediatr Allergy Immunol 32:1804-1812.
2. He R et al (2021) Identification of a Long Noncoding RNA TRAF3IP2-AS1 as Key Regulator of IL-17 Signaling through the SRSF10-IRF1-Act1 Axis in Autoimmune Diseases. J Immunol 206:2353-2365.
3. Lambert S et al (2017) Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses. J Invest Dermatol 137:1501-1511.
4. Shi R et al (2021) N6-Methyladenosine-Related Long Noncoding RNAs as Potential Prognosis Biomarkers for Endometrial Cancer. Int J Gen Med 14:8249-8262.